title: Fuz mutant mice reveal shared mechanisms between ciliopathies and FGF-related syndromes.
abstract: Ciliopathies are a broad class of human disorders with craniofacial dysmorphology as a common feature. Among these is high arched palate, a condition that affects speech and quality of life. Using the ciliopathic Fuz mutant mouse, we find that high arched palate does not, as commonly suggested, arise from midface hypoplasia. Rather, increased neural crest expands the maxillary primordia. In Fuz mutants, this phenotype stems from dysregulated Gli processing, which in turn results in excessive craniofacial Fgf8 gene expression. Accordingly, genetic reduction of Fgf8 ameliorates the maxillary phenotypes. Similar phenotypes result from mutation of oral-facial-digital syndrome 1 (Ofd1), suggesting that aberrant transcription of Fgf8 is a common feature of ciliopathies. High arched palate is also a prevalent feature of fibroblast growth factor (FGF) hyperactivation syndromes. Thus, our findings elucidate the etiology for a common craniofacial anomaly and identify links between two classes of human disease: FGF-hyperactivation syndromes and ciliopathies.
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, Dental Institute, King's College London, London SE1 9RT, UK.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tabler
authors.forename: William B
authors.initials: WB
authors.lastname: Barrell
authors.forename: Heather L
authors.initials: HL
authors.lastname: Szabo-Rogers
authors.forename: Christopher
authors.initials: C
authors.lastname: Healy
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Yeung
authors.forename: Elisa Gomez
authors.initials: EG
authors.lastname: Perdiguero
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Basil Z
authors.initials: BZ
authors.lastname: Yannakoudakis
authors.forename: Aida
authors.initials: A
authors.lastname: Mesbahi
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: John B
authors.initials: JB
authors.lastname: Wallingford
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000473:pathology; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008437:Maxilla / Q000002:abnormalities; D051379:Mice; D008817:Mice, Mutant Strains; D009432:Neural Crest / Q000002:abnormalities; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000473:pathology; D010159:Palate / Q000002:abnormalities; D010641:Phenotype; D000071676:Zinc Finger Protein GLI1
chemical_list: D003598:Cytoskeletal Proteins; C496457:Fgf8 protein, mouse; C544812:Fuz protein, mouse; C498520:Gli1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051524:Fibroblast Growth Factor 8